Cutaneous appendages, the hair follicles and sweat glands, underwent dramatic change as humans evolved from primate ancestors. Analyses of genetic divergence reveal ongoing selection on genes that regulate cutaneous appendage development within human populations. The parent grant for this supplemental application is designed to identify genes that mediate inductive signaling to initiate hair follicle development and guide morphogenesis in the mouse. The proposed research extends that analysis in two ways. First, a specific amino acid substitution in the Ectodysplasin receptor, a component of a signaling pathway important for both hair and sweat gland development, has been selected for in East Asians and Native Americans. In collaboration with the systems biologist that identified this allele, we created a mouse model of the derived human allele and will study its function in the mouse. The second goal uses systems biology approaches to identify genes that regulate the density of hair follicles and sweat glands in the mouse, and to determine if mechanisms that regulate the densities of these two appendages are intricately linked. This basic team of systems biologists studying signatures of recent selection within the human genome and an expert in analyzing the role of genes in cutaneous appendage development in mice is augmented by an expert on the role of cutaneous appendages in early human evolution and a leader in the use of comparative approaches in developmental biology. With this interdisciplinary research team we extend the analysis in the parent grant to an additional cutaneous appendage, the eccrine sweat gland, apply new approaches made possible by the expertise of our collaborators, and focus our analysis in the mouse on the genes most important for human cutaneous appendage divergence. The successful completion of this work will have application in improved wound healing and skin grafts, and in the understanding and treatment of disorders of cutaneous appendages including anhydrotic/hypohydrotic ectodermal dysplasias and alopecias. It will also contribute to our understanding of how genetic variation within the human population contributes to unique properties of the skin and its appendages in different populations. PUBLIC HEALTH RELEVANCE: Humans have sparse body hair and high densities of sweat glands compared to other mammals. This research is designed to understand the genetic regulation of hair follicle and sweat gland formation and the way that the changes of these two independent mini-organs are linked. The function of newly discovered variants of genes that regulate the formation of these organs and are enriched in different human populations will be tested in mice, and the approaches of genome analysis will be applied to identify genes that regulate a dramatic shift in the relative density of hair follicles and sweat glands in mice. This will guide our analysis of genetic variation in humans that may affect distinctive hair and sweat gland biology.